COVID-19 vaccination and hybrid immunity in older adults
Authors: Jorge G Ruiz, Melissa K Andrew
Journal: The Lancet Healthy Longevity (2023)

Older adults are at a higher risk of severe illness from COVID-19. Vaccines reduce the risk of infection, severe complications, hospitalisation, and death. However, compared with younger individuals, older adults have both an increased vulnerability to adverse outcomes from infection and a diminished response to vaccination.1Andrew MK McElhaney JE Age and frailty in COVID-19 vaccine development.Lancet. 2021; 396: 1942-1944Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar Host factors, including immune changes with ageing immunosenescence and underlying health status, might lead to less effective responses. Older adults receiving COVID-19 vaccines generate a diminished production of antibodies and T-cell activation, which translates into lower vaccine effectiveness.2Andrews N Tessier E Stowe J et al.Duration of protection against mild and severe disease by Covid-19 vaccines.N Engl J Med. 2022; 386: 340-350Crossref PubMed Scopus (378) Google Scholar Moreover, previous infection might generate immune responses that increase the variability of vaccine responses. It is important to understand the contributors to this heterogeneity, which is not well addressed by universal age-based immunisation recommendations. Efforts at personalising vaccination to accommodate variable age-related immune responses might be a promising approach to optimise protection. In The Lancet Healthy Longevity, Sara Carazo and colleagues3Carazo S Skowronski DM Brisson M et al.Effectiveness of previous infection-induced and vaccine-induced protection against hospitalisation due to omicron BA subvariants in older adults: a test-negative, case-control study in Quebec, Canada.Lancet Healthy Longev. 2023; (published online July 14.)https://doi.org/10.1016/S2666-7568(23)00099-5Summary Full Text Full Text PDF Scopus (4) Google Scholar used a test-negative, case-control design to compare the protective effects of previous infection, vaccination, and hybrid immunity against omicron-related hospitalisations. The population was community-dwelling adults aged 60 years and over living in the province of Quebec, Canada, during a period of predominant omicron subvariants. They found that the combination of infection and vaccination was the most protective against hospitalisation and was associated with higher and more sustained duration of protection (>90%) for at least 8 months after infection or after the last vaccine dose. The study findings might have public health implications regarding the need for additional boosters to maintain high levels of protection over time, with booster doses appearing to be less important for those with hybrid immunity versus immunity from vaccines alone. The ageing process is characterised by interindividual variability in immune function and responses to vaccination. Although some older adults have robust immune responses, individuals with frailty might not respond as well.1Andrew MK McElhaney JE Age and frailty in COVID-19 vaccine development.Lancet. 2021; 396: 1942-1944Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 4Andrew MK Schmader KE Rockwood K Clarke B McElhaney JE Considering frailty in SARS-CoV-2 vaccine development: how geriatricians can assist.Clin Interv Aging. 2021; 16: 731-738Crossref PubMed Scopus (12) Google Scholar Frailty is a common age-related condition characterised by reduced reserves and vulnerability caused by multisystemic dysfunction. Individuals who are frail have a higher risk of severe illness and mortality from COVID-19.5Dumitrascu F Branje KE Hladkowicz ES Lalu M McIsaac DI Association of frailty with outcomes in individuals with COVID-19: a living review and meta-analysis.J Am Geriatr Soc. 2021; 69: 2419-2429Crossref PubMed Scopus (59) Google Scholar The evidence regarding the effect of frailty on COVID-19 vaccine responses is emerging. Frailty was an independent predictor of in-vitro impaired antibody responses to mRNA vaccines in men older than 55 years.6Semelka CT DeWitt ME Callahan KE et al.Frailty and COVID-19 mRNA Vaccine Antibody Response in the COVID-19 Community Research Partnership.J Gerontol A Biol Sci Med Sci. 2022; 77: 1366-1370Crossref PubMed Scopus (11) Google Scholar A few observational studies have shown that with increasing frailty, vaccine effectiveness against infection, hospitalisation, and death is reduced.7Tang F Hammel IS Andrew MK Ruiz JG COVID-19 mRNA vaccine effectiveness against hospitalisation and death in veterans according to frailty status during the SARS-CoV-2 delta (B.1.617.2) variant surge in the USA: a retrospective cohort study.Lancet Healthy Longev. 2022; 3: e589-e598Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 8Tang F Hammel IS Andrew MK Ruiz JG Frailty reduces vaccine effectiveness against SARS-CoV-2 infection: a test-negative case control study using national va data.J Nutr Health Aging. 2023; 27: 81-88PubMed Google Scholar Frail older adults are not often included in clinical trials, which is another important contributor to this evidence gap.4Andrew MK Schmader KE Rockwood K Clarke B McElhaney JE Considering frailty in SARS-CoV-2 vaccine development: how geriatricians can assist.Clin Interv Aging. 2021; 16: 731-738Crossref PubMed Scopus (12) Google Scholar Before embarking on future studies, a few issues must be considered. Efforts to broadly define study populations and inclusion criteria, such that frail people are not excluded, and integration of frailty assessments into vaccine studies will help address the challenge of predicting the effectiveness and duration of hybrid immunity, given the known age-related heterogeneity of immune responses to previous infection and vaccination.1Andrew MK McElhaney JE Age and frailty in COVID-19 vaccine development.Lancet. 2021; 396: 1942-1944Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 4Andrew MK Schmader KE Rockwood K Clarke B McElhaney JE Considering frailty in SARS-CoV-2 vaccine development: how geriatricians can assist.Clin Interv Aging. 2021; 16: 731-738Crossref PubMed Scopus (12) Google Scholar Studies of older residents in nursing homes with previous infection revealed that single doses of mRNA vaccine generated levels of IgG antibodies similar to two doses in those who were naive to infection, but antibody responses did not correlate with frailty.9Salmerón Ríos S Mas Romero M Cortés Zamora EB et al.Immunogenicity of the BNT162b2 vaccine in frail or disabled nursing home residents: COVID-A study.J Am Geriatr Soc. 2021; 69: 1441-1447Crossref PubMed Scopus (58) Google Scholar, 10Seiffert P Konka A Kasperczyk J et al.Immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in older residents of a long-term care facility: relation with age, frailty and prior infection status.Biogerontology. 2022; 23: 53-64Crossref PubMed Scopus (14) Google Scholar In addition to small samples, the absence of a correlation might reflect instrument limitations in detecting differences between predominantly frail residents. The inclusion of a wider spectrum of participants from robust to frail might demonstrate an association. Furthermore, although humoral immunity might be essential for avoiding infection, the combination of humoral and cellular immunity prevents serious disease.1Andrew MK McElhaney JE Age and frailty in COVID-19 vaccine development.Lancet. 2021; 396: 1942-1944Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 6Semelka CT DeWitt ME Callahan KE et al.Frailty and COVID-19 mRNA Vaccine Antibody Response in the COVID-19 Community Research Partnership.J Gerontol A Biol Sci Med Sci. 2022; 77: 1366-1370Crossref PubMed Scopus (11) Google Scholar As such, it is important to consider measures of cell-mediated immunity in vaccine studies. Frail individuals might not generate an effective post-infection response, hindering hybrid immunity contributions to vaccine effectiveness. Another crucial issue is the duration of immunity, which might require either higher vaccine doses or additional boosters for frail people. Studies of boosters that consider frailty and examine vaccine effectiveness according to history of previous infection (recognising the challenge of confirming infection) might provide some answers. Vaccine product formulation and dose could be optimised to stimulate immune responses. This will not be possible unless age and frailty are intentionally considered in studies informing product design and comparative vaccine effectiveness evaluations.4Andrew MK Schmader KE Rockwood K Clarke B McElhaney JE Considering frailty in SARS-CoV-2 vaccine development: how geriatricians can assist.Clin Interv Aging. 2021; 16: 731-738Crossref PubMed Scopus (12) Google Scholar These studies can be complemented by investigations of in-vitro humoral and cellular responses. Future studies might provide a deeper understanding of the effects of previous infection, vaccine dose and formulation, and boosters in older individuals with frailty. The need for booster programmes in older adults, especially those who are frail, must be continually evaluated, and recommendations from health authorities should be expected to evolve based on scientific evidence. A personalised approach to COVID-19 vaccination represents a desirable and promising opportunity to enhance protection for those most vulnerable; however, more work is needed to ensure that this is evidence-informed and feasible. JGR reports consulting fees from Pfizer and grant funding from Longeveron. MKA reports grant support from GlaxoSmithKline, Sanofi, Pfizer, Public Health Agency of Canada, Canadian Institutes of Health Research, COVID-19 Immunity Task Force, and Canadian Frailty Network; past honoraria for ad-hoc advisory activities from Sanofi, Pfizer, and Seqirus; and is a member of Canada's National Advisory Committee on Immunization. Effectiveness of previous infection-induced and vaccine-induced protection against hospitalisation due to omicron BA subvariants in older adults: a test-negative, case-control study in Quebec, CanadaOlder adults with both previous SARS-CoV-2 infection and two or more vaccine doses appear to be well protected for a prolonged period against hospitalisation due to omicron subvariants, including BA.4/5. Ensuring that older adults who are infection naive remain up to date with vaccination might reduce COVID-19 hospitalisations most efficiently. Full-Text PDF Open Access